Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: anti-inflammatory and analgesic activities

Amer M Alanazi; Adel S El-Azab; Ibrahim A Al-Suwaidan; Kamal Eldin H ElTahir; Yousif A Asiri; Naglaa I Abdel-Aziz; Alaa A-M Abdel-Aziz

doi:10.1016/j.ejmech.2014.12.039

Structure-based design of phthalimide derivatives as potential cyclooxygenase-2 (COX-2) inhibitors: anti-inflammatory and analgesic activities

Eur J Med Chem. 2015 Mar 6:92:115-23. doi: 10.1016/j.ejmech.2014.12.039. Epub 2014 Dec 24.

Authors

Amer M Alanazi¹, Adel S El-Azab², Ibrahim A Al-Suwaidan¹, Kamal Eldin H ElTahir³, Yousif A Asiri⁴, Naglaa I Abdel-Aziz⁵, Alaa A-M Abdel-Aziz⁶

Affiliations

¹ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
² Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
³ Department of Pharmacology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁴ Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; Department of Medicinal Chemistry, Faculty of Pharmacy, University of Mansoura, Mansoura 35516, Egypt. Electronic address: alaa_moenes@yahoo.com.

PMID: 25549551
DOI: 10.1016/j.ejmech.2014.12.039

Abstract

A group of 30 cyclic imides (1-10a-c) was designed for evaluation as a selective COX-2 inhibitor and investigated in vivo for anti-inflammatory and analgesic activities. Compounds 6a, 6b, 7a and 7b exhibit optimal COX-2 inhibitory potency (IC50 = 0.18, 0.24, 0.28 and 0.36 μM; respectively) and selectivity index (SI) range of 363-668. In vitro COX-1/COX-2 inhibition structure-activity studies identified compound 6a as a highly potent (IC50 = 0.18 μM), and an extremely selective [COX-2 (SI) = 668] comparable to celecoxib [COX-2 (SI) > 384], COX-2 inhibitor that showed superior anti-inflammatory activity (ED50 = 54.0 mg/kg) relative to diclofenac (ED50 = 114 mg/kg). Molecular Docking study of the synthesized compound 6a into the active site of COX-2 revealed a similar binding mode to SC-558, a selective COX-2 inhibitor. Docking study showed that the methoxy moeities of 6a inserted deep inside the 2°-pocket of the COX-2 active site, where the O-atoms of such groups underwent an H-bonding interaction with His(90) (3.02 Å), Arg(513) (1.94, 2.83 Å), and Gln(192) (3.25 Å).

Keywords: Analgesic activity; Anti-inflammatory activity; COX-2 inhibitors; Molecular docking; Phthalimides.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry
Analgesics / pharmacology*
Animals
Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis
Anti-Inflammatory Agents, Non-Steroidal / chemistry
Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
Carrageenan
Cyclooxygenase 2 Inhibitors / chemical synthesis
Cyclooxygenase 2 Inhibitors / chemistry
Cyclooxygenase 2 Inhibitors / pharmacology*
Drug Design*
Edema / chemically induced
Edema / drug therapy
Male
Models, Molecular
Molecular Structure
Phthalimides / chemical synthesis
Phthalimides / chemistry
Phthalimides / pharmacology*
Rats
Rats, Sprague-Dawley

Substances

Analgesics
Anti-Inflammatory Agents, Non-Steroidal
Cyclooxygenase 2 Inhibitors
Phthalimides
phthalimide
Carrageenan